Opioids Flashcards
What is an opiate?
Anything that comes from the opium poppy. An opiate is an alkaloid derived from the poppy, Papaver somniferum.
What are the 4 most common natural opiates?
morphine, codeine, thebaine and papaverine
What is an opioid?
Synthetic or natural (opiates are natural opioids)
How are opioids/opiates administered?
oral or intravenous administration (usually), therapeutically given orally but abusive users use IV
What is the bioavailability with IV?
IV - 100% bioavailability
Are opioids well absorbed in the stomach and why?
What about in the small intestine and why?
Opioids are weak bases – pKa >8 – so they won’t be very unionised in the stomach (-> poor absorption)
However, once they enter the small intestines, they are well absorbed (alkaline environment)
Describe the solubility of different opioids in comparison to morphine
Lipid solubility is important in terms of how effective the drugs are. Morphine has a potency of 1:1 so we are using this as our comparator.
Heroine is around twice as soluble as morphine, and this contributes to potency. Codeine is a little bit more lipid soluble than morphine, but is considerably less potent.
General rule of thumb – the more lipid soluble, the more potent (exception: codeine)
Lipid Solubility: Methadone/Fentanyl»_space; Heroin > Morphine
Active metabolite of morphine?
- Morphine-6-glucoronide is the most potent active metabolite of morphine (10% of the blood levels of morphine at any one time).
Morphine seems more likely to cause the negative side effects (e.g. respiratory depression). The active metabolites are less likely to do this
What happens to individuals who cannot metabolise morphine well?
Individuals who don’t metabolise morphine very well are more likely to have negative side effects.
How fast is fentanyl metabolised?
Fentanyl is metabolised by cytochrome 3A4 quickly, and is cleared equally fast. Therefore, fentanyl has a fast effect, but the effect is also quickly lost.
How fast is methadone metabolised?
Methadone is metabolised by several enzymes – so metabolism is quite slow and the drug isn’t cleared well from the body.
Why is methadone used as a heroin replacement?
Methadone and fentanyl are very lipid soluble. Because methadone is cleared slowly, it can accumulate in fatty tissues. This is one of the reasons why methadone is used as heroine replacement (it persists in the body for longer – 24 hour clearance profile).
How is codeine metabolised?
- Codeine is metabolised by two cytochrome P450 enzymes
- One enzyme activates codeine (CYP2D6) to morphine – 5-10% of the codeine is converted via this route
- The other enzyme (CYP3A4) deactivates codeine – all conversion takes place in the liver
What do opioids act on?
They act via specific ‘opioid’ receptors
Which endogenous molecules act on the opioid receptor?
- Endorphins
- Enkephalins
- Dynorphins/neoendorphins
What are the 3 types of opioid receptors and what acts on them, where are they found and what are they important in?
Endorphins act on Mu (μ) receptors or delta (δ) receptors
- Located in the cerebellum, caudate nucleus, nucleus accumbens and PAG
- Important in pain and sensation
Enkephalins act on delta (δ) receptors
- Located in the nucleus accumbens, cerebral cortex, hippocampus and putamen
- Important in motor and cognitive function
Dynorphins act on kappa (κ) receptors
- Located in the hypothalamus, putamen and caudate
- Important neuroendocrine role (via the hypothalamus)
Where do endorphins act?
Mu (μ) receptors or delta (δ) receptors
- Located in the cerebellum, caudate nucleus, nucleus accumbens and PAG
- Important in pain and sensation
How do opioid receptors work when activated? (cellular mechanism)
Opioids are depressant – they tend to slow cellular activity
- They can hyperpolarise cells -> hyperpolarisation (increase K+ efflux)
- They can reduce the Ca2+ inward current – this massively impacts exocytosis and NT release
- Within the cell, they can decrease adenylate cyclase activity
What effects do opioids have?
- Analgesia
- Euphoria
- Depression of cough centre (anti-tussive)
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary Constriction
- G.I. Effects
How do opioids cause euphoria?
Opioids enter the brain and bind to their receptors. They depress the firing rate of GABA interneurons.
This is, again, a process of disinhibition. This means that the dopaminergic neurone increases its firing rate -> increased dopamine secretion -> feelings of reward
Structure of morphine
- The tertiary form nitrogen appears to be crucial to the analgesic effect. Making nitrogen quaternary appears to decrease the analgesic effect greatly (since it cannot pass into the CNS)
- The tertiary nitrogen permits receptor anchoring
- 2 OH groups to help with stabilising
How is the structure of morphine changed to create antagonists?
- Extending the side chain (3+ C)
- Changes to the methyl group will also decrease the analgesic effect
Compare the structure of heroin and codeine to morphine
- Heroin has two acetyl groups instead of 2 OH groups
- Codeine has a methyl attached to the oxygen of the O(H)
What are 2 other drugs that are similar to morphine?
methadone (tertiary nitrogen) and fentanyl (two tertiary nitrogens)
Heroin and codein solubility
- The hydroxyl group at position 3 – required for bind
- Codeine must undergo some metabolism to become activated and reveal its hydroxyl group
- The hydroxyl group at position 6 – when in oxidised form, the lipophilicity of the drug increases 10-fold
Why do heroin and codeine have to be converted to morphine? Where does this happen for each of them?
- Heroine and codeine are more lipid soluble than morphine
- In theory, they should get across the BBB more easily
- However, the hydroxyl groups associated with morphine are needed for activity
- As a result, heroine and codeine have to be converted to morphine to exert an effect
- For heroine, this conversion can happen in the brain
- This is not the case for codeine (codeine -> morphine conversion must take place outside the brain).
OPIODS AND PAIN
USE SLIDES AND DIAGRAM
How do opioids have anti-tussive effects?
Opioids cause 3 effects to supress coughing (centrally and peripherally):
Central:
- 5HT1A-receptor antagonist:
5HT1A-receptor is a negative feedback receptor for serotonin and firing leads to suppression of serotonin and activation of the cough reflex
Inhibition of this receptor increases serotonin so less cough
- Medulla direct depression
Peripheral:
- ACh and NK (Neurokinin) release inhibition so less transmission down the sensory nerves to the vagus afferents
How do opioids cause respiratory depression?
- Depression of the Pre-Botzinger complex in the ventrolateral medulla – this generates respiratory rhythm so less rhythm with depression
- Central chemoreceptors are also inhibited by opioids and so depress the firing rate of the central chemoreceptors
How do opioids cause nausea and vomiting?
- Low-dose opioids activate Mu receptors in the CTZ (Chemoreceptor Trigger Zone) and stimulate vomiting
- The Mu receptor stimulates disinhibition by switching off GABA secretion
How do opioids cause mioisis?
Opioids cause pin-point pupils. Opioid receptors are expressed in the Edinger-Westphal nucleus and therefore influence miosis.
The optic nerve is the sensory nerve that relays information to the pretectal nucleus. Signals are transmitted to parasympathetic nerves in the EWN. Opioids can influence the parasympathetic nerves here. GABA suppress the parasympathetic nerves – opioids switch inhibition off -> miosis
How do opioids affect the enteric nervous system and cause gut problems?
- There are opioid receptors everywhere within the enteric nervous system
- As a result, they prevent sensory information being relayed in
- Opioids also affect motor function -> heavy constipation due to suppression of enteric NS
- There is less gut contraction and fewer secretions
Opioids and urticaria
Urticarial reaction may result from opioids – it is controlled by histamine release, but it is not an allergic response. It results from a direct interaction of opioids with mast cells -> causes histamine release. It seems to involve PKA, and doesn’t seem to involve opioid receptors. It is caused by morphine and codeine mainly.
What causes opioid tolerance?
- You become tolerant to opioids but this is nothing to do with the liver and pharmacokinetics
- Tolerance comes about at the level of tissues – receptor internalisation
- Arrestin: a very important protein in terms of driving receptor internalisation – constant recycling
- If opioids are constantly available, cells are suppressed -> opioid receptors are withdrawn from the cell
- The arrestin protein concentration increases -> increased internalisation -> tolerance
What happens in opioid withdrawal?
Withdrawal is associated with psychological craving, but there is also physical withdrawal (flu-like). Cells try to upregulate activity (increase in adenylate cyclase). Once opioids are removed, adenylate cyclase is overactive.
What happens due to opioid overdose?
- Coma
- Respiratory depression
- Pin-point pupils
- Hypotension
Treatment: give naloxone (opioid antagonist)
Where are opioids metabolised?
Are they mostly ionised or unionised?
- Opioids are heavily metabolised in the liver (first pass) – this impacts their bioavailability
- Because the pH of the blood is around 7.4, opioids are largely ionised in the blood (80%)
- Only 20% of opioids remain unionised (unionised form accesses tissues readily – more lipophilic)
Enteric nervous system structure
- Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food
- Information relayed to submucosal and myenteric plexus via interneurons
- Motor neurones release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle
Compare the speed of fenatanyl and methadone metabolism
Fentanyl (fast metabolism) vs. Methadone (slow metabolism)
